ProjectReconstructing a dated tree of life using phylogenetic incongruence

Researcher (PI)Gergely Janos SZOLLOSI

Host Institution (HI)EOTVOS LORAND TUDOMANYEGYETEM

Call DetailsStarting Grant (StG), LS8, ERC-2016-STG

SummaryWith the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.

With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.

Max ERC Funding

1 453 542 €

Duration

Start date: 2017-07-01, End date: 2022-06-30

Project acronymMulticellularity

ProjectThe genetic basis of the convergent evolution of fungal multicellularity

SummaryThe evolution of multicellularity (MC) has been one of the major transitions in the history of life. Despite immense interest in its evolutionary origins, the genomic changes leading to the emergence of MC, especially that of complex MC (differentiated 3-dimensional structures) are poorly known. Previous comparative genomics projects aiming to understand the genetic bases of MC in one way or another relied on gene content-based analyses. However, a pattern emerging from these studies is that gene content provides only an incomplete explanation for the evolution of MC even at ancient timescales. We hypothesize that besides gene duplications, changes to cis-regulatory elements and gene expression patterns (including protein isoforms) have significantly contributed to the evolution of MC. To test this hypothesis, we will deploy a combination of computational methods, phylogenomics, comparative transcriptomics and genome-wide assays of regulatory elements. Our research focuses on fungi as a model system, where complex MC evolved convergently and in subsequent two steps. Fungi are ideal models to tackle this question for several reasons: a) multicellularity in fungi evolved multiple times, b) there are rich genomic resources (>500 complete genomes), c) complex multicellular structures can be routinely grown in the lab and d) genetic manipulations are feasible for several cornerstone species. We set out to examine which genes participate in the building of simple and complex multicellular structures and whether the evolution of regulome complexity and gene expression patterns can explain the evolution of MC better than can traditionally assayed sources of genetic innovations (e.g. gene duplications). Ultimately, our goal is to reach a general synthesis on the genetic bases of the evolution of MC and that of organismal complexity.

The evolution of multicellularity (MC) has been one of the major transitions in the history of life. Despite immense interest in its evolutionary origins, the genomic changes leading to the emergence of MC, especially that of complex MC (differentiated 3-dimensional structures) are poorly known. Previous comparative genomics projects aiming to understand the genetic bases of MC in one way or another relied on gene content-based analyses. However, a pattern emerging from these studies is that gene content provides only an incomplete explanation for the evolution of MC even at ancient timescales. We hypothesize that besides gene duplications, changes to cis-regulatory elements and gene expression patterns (including protein isoforms) have significantly contributed to the evolution of MC. To test this hypothesis, we will deploy a combination of computational methods, phylogenomics, comparative transcriptomics and genome-wide assays of regulatory elements. Our research focuses on fungi as a model system, where complex MC evolved convergently and in subsequent two steps. Fungi are ideal models to tackle this question for several reasons: a) multicellularity in fungi evolved multiple times, b) there are rich genomic resources (>500 complete genomes), c) complex multicellular structures can be routinely grown in the lab and d) genetic manipulations are feasible for several cornerstone species. We set out to examine which genes participate in the building of simple and complex multicellular structures and whether the evolution of regulome complexity and gene expression patterns can explain the evolution of MC better than can traditionally assayed sources of genetic innovations (e.g. gene duplications). Ultimately, our goal is to reach a general synthesis on the genetic bases of the evolution of MC and that of organismal complexity.

Max ERC Funding

1 486 500 €

Duration

Start date: 2018-01-01, End date: 2022-12-31

Project acronymresistance evolution

ProjectBacterial evolution of hypersensitivity and resistance against antimicrobial peptides

SummaryEvolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.

Evolution of resistance towards a single drug simultaneously increases (cross-resistance) or decreases (collateral sensitivity) fitness to multiple other antimicrobial agents. The molecular mechanisms driving cross-resistance are relatively well described, but it remains largely unclear how frequently does genetic adaptation to a single drug increase the sensitivity to others and what the underlying molecular mechanisms of collateral sensitivity are. This proposal focuses on studying the bacterial evolution of resistance and collateral sensitivity against antimicrobial peptides (AMPs). Beyond their modulatory roles in the immune system, these naturally occurring peptides provide protection against pathogenic microbes, and are considered as promising novel alternatives to traditional antibiotics. However, there are concerns that evolution against therapeutic AMPs can readily develop and as a by-product this might compromise natural immunity. Our knowledge of these issues is limited due to the shortage of systematic evolutionary studies. Therefore, the three central questions we address are: Do bacteria resistant to multiple antibiotics become hypersensitive to certain antimicrobial peptides? What are the evolutionary mechanisms leading to AMP resistance and to what extent does this process induce cross-resistance/collateral sensitivity against other drugs? Last, are these evolutionary trade-offs predictable based on chemical and functional peptide properties? To investigate these issues rigorously, we integrate tools of laboratory evolution, high-throughput phenotypic assays, functional genomics, and computational systems biology. Our project will provide an insight into the evolutionary mechanisms that drive cross-resistance and collateral sensitivities with the aim to explore the vulnerable points of resistant bacteria. Another goal is to provide guidelines for the future design of antimicrobial peptides with desirable properties against bacterial pathogens.